CNTF Negatively Regulates the Phototransduction Machinery in Rod Photoreceptors: Implications for Light-Induced Photostasis Plasticity

Abstract

Purpose:: CNTF promotes photoreceptor survival, but also suppresses ERG (electroretinogram) responses. This has caused concern about whether CNTF is detrimental to the function of photoreceptors since it is considered to be a potential treatment for retinal degenerative disorders. The present work explores the mechanism by which CNTF inhibits ERG responses.

Methods:: Recombinant human CNTF was delivered by intravitreal injection in adult Long Evans rats. The left eye of an animal was injected with CNTF (10 µg in 5 µl PBS), and the right eye with PBS (5 µl). ERG recording was performed after injection. For light exposure experiments, animals were exposed to an in-cage illuminance of 400 lx for 10 hr daily for 7 days with pupils dilated. The levels of phototransduction related proteins were examined by Western blotting. The morphology of rod outer segments was examined by light and electron microscopy.

Results:: Intravitreal injection of CNTF protein reversibly supresses the amplitudes of ERG a- and b-wave. It also induces in a series of biochemical and morphological changes in rods. CNTF induces a decrease in rhodopsin expression and an increase in arrestin level. Similar changes were found in light exposed animals. Morphologically, CNTF induced a significant shortening of rod outer segments (ROS), as did light exposure. All CNTF induced changes are fully reversible. CNTF induced a dramatic increase in STAT3 phosphorylation in Müller cells, but not in photoreceptors, indicating that photoreceptors are not directly responsive to CNTF.

Conclusions:: The net effect of CNTF is a reduction in rod photoresponsiveness, resulting in lower amplitude ERG waves. The morphological and biochemical changes produced by CNTF are similar to those in light-induced photoreceptor plasticity, a phenomenon explained by the photostasis hypothesis. Our present work suggests that CNTF and light regulate the phototransduction machinery through the same mechanism and that Müller cells play an essential role in mediating both the CNTF and light effects.

Keywords: photoreceptors • growth factors/growth factor receptors • Muller cells